Pharmaceutical compositions

ABSTRACT

A pharmaceutical solution for a medication delivery apparatus, especially a metered dose inhaler, is described. The pharmaceutical solution comprises: (a) a liquefied propellant component consisting essentially of and preferably consisting entirely of 1,1-difluoroethane (R-152a); (b) ethanol; and (c) a drug component dissolved in the propellant/ethanol mixture consisting of at least one drug selected from the group consisting of beclomethasone dipropionate (BDP) and fluticasone propionate (FP).

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/117,340, filed May 12, 2014 which is the U.S. National Phaseunder 35 U.S.C. §371 of International Application No. PCT/GB2012/051059,filed May 11, 2012, designating the United States and published inEnglish on Nov. 22, 2012, as WO 2012/156711, which claims priority toUnited Kingdom Application No. 1108039.7, filed May 13, 2011, which isincorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition comprisinga drug, 1,1-difluoroethane (R-152a) propellant and ethanol that issuitable for delivering the drug, especially from a pressurised aerosolcontainer using a metered dose inhaler (MDI).

BACKGROUND

MDIs are the most significant type of inhalation drug delivery systemand are well known to those skilled in the art. They are designed todeliver, on demand, a discrete and accurate amount of a drug to therespiratory tract of a patient using a liquefied propellant in which thedrug is dissolved, suspended or dispersed. The design and operation ofMDIs is described in many standard textbooks and in the patentliterature. However, they all comprise a pressurised container thatholds the drug formulation, a nozzle and a valve assembly that iscapable of dispensing a controlled quantity of the drug through thenozzle when it is activated. All of these components are typicallylocated in a housing that is equipped with a mouth piece. The drugformulation will comprise a propellant, in which the drug is dissolved,suspended or dispersed, and may contain other materials such asco-solvents, surfactants and preservatives.

In order for a propellant to function satisfactorily in MDIs, it needsto have a number of properties. These include an appropriate boilingpoint and vapour pressure so that it can be liquefied in a closedcontainer at room temperature but develop a high enough pressure whenthe MDI is activated to deliver the drug as an atomised formulation evenat low ambient temperatures. Further, the propellant should be of lowacute and chronic toxicity and have a high cardiac sensitisationthreshold. It should have a high degree of chemical stability in contactwith the drug, the container and the metallic and non-metalliccomponents of the MDI device, and have a low propensity to extract lowmolecular weight substances from any elastomeric or other polymericmaterials in the MDI device. The propellant should also be capable ofmaintaining the drug in a homogeneous solution, in a stable suspensionor in a stable dispersion for a sufficient time. When the drug is insuspension in the propellant, the density of the liquid propellant isdesirably similar to that of the solid drug in order to avoid rapidsinking or floating of the drug particles in the liquid. Finally, thepropellant should not present a significant flammability risk to thepatient in use. In particular, it should form a non-flammable or lowflammability mixture when mixed with air in the respiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination ofproperties and was for many years the most widely used MDI propellant,often blended with trichlorofluoromethane (R-11). Due to internationalconcern that fully and partially halogenated chlorofluorocarbons (CFCs),such as dichlorodifluoromethane and trichlorofluoromethane, weredamaging the earth's protective ozone layer, many countries entered intoan agreement, the Montreal Protocol, stipulating that their manufactureand use should be severely restricted and eventually phased outcompletely. Dichlorodifluoromethane and trichlorofluoromethane werephased out for refrigeration use in the 1990's, but are still used, tosome extent, in the MDI sector as a result of an essential use exemptionin the Montreal Protocol.

1,1,1,2-tetrafluoroethane (R-134a) was introduced as a replacementrefrigerant and MDI propellant for R-12.1,1,1,2,3,3,3-heptafluoropropane (R-227ea) was also introduced as areplacement for R-12 in the fire control (e.g. computer suites) and MDIsectors and is sometimes blended with R-134a for these applications.

Although R-134a and R-227ea have low ozone depletion potentials (ODPs),they have global warming potentials (GWPs), 1430 and 3220 respectively,that are now considered to be too high by some regulatory bodies,especially for dispersive uses when they are released into theatmosphere.

One industrial area that has received particular attention recently hasbeen the automotive air-conditioning sector where the use of R-134a hascome under regulatory control as a result of the European F-GasRegulations. Industry is developing a number of possible alternatives toR-134a in automotive air conditioning and other applications that have alow greenhouse warming potential (GWP) as well as a low ozone depletionpotential (ODP). Many of these alternatives include hydrofluoropropenes,especially the tetrafluoropropenes such as 2,3,3,3-tetrafluoropropene(R-1234yf) and 1,3,3,3-tetrafluoropropene (R-1234ze).

Although the proposed alternatives to R-134a have a low GWP, thetoxicological status of many of the components, such as certain of thefluoropropenes, is unclear and they are unlikely to be acceptable foruse in the MDI sector for many years, if at all.

There are also other problems with R-134a and R-227ea. Mostpharmaceutical actives for treating respiratory disorders, such asasthma, tend not to dissolve well in either R-134a or R-227ea and haveto be handled as suspensions in the propellant. Drug suspensions giverise to a number of problems, such as nozzle blockage, agglomeration andsedimentation, the latter problem making it essential to shake the MDIthoroughly before use to ensure that the drug is evenly distributed inthe propellant. Furthermore, if the pharmaceutical active settlesquickly following re-suspension in the propellant, as is often the case,then the propellant/drug composition must be delivered from the MDIshortly after shaking in order to ensure that the dose that is deliveredcontains an effective concentration of the pharmaceutical active.

The problem of poorly dissolving drugs has been addressed by including acarrier solvent in the composition in which the drug is soluble, such asethanol, and/or by adding a surfactant to the composition to produce amore stable suspension. However, neither of these solutions is ideal. Inparticular, they can tend to impair the efficiency of the atomisationprocess and the quality of the aerosol spray that is delivered from theMDI. For example, carrier solvents such as ethanol can tend to result ina coarse spray having droplet sizes that are too large for acceptablepenetration into the deep bronchiole passages of the lung. Further, highlevels of ethanol can have unacceptable irritancy to the mouth andthroat, especially with younger users. Clearly it would be advantageousto use the minimum levels of ethanol required in order to produce anacceptable solution formulation.

There is a need for a MDI aerosol formulation that has a reduced GWP incomparison with R-134a and R-227ea, that has acceptable flammability andtoxicity performance and which forms stable suspensions or solutionswith a range of pharmaceutical actives and with reduced irritancy.

SUMMARY

According to a first aspect, the present invention provides for the useof a propellant consisting essentially of and preferably consistingentirely of 1,1-difluoroethane (R-152a) in a pharmaceutical compositioncomprising a drug, the propellant and ethanol in order to reduce theamount of ethanol required for dissolving the drug in the pharmaceuticalcomposition compared to the amount that would be needed if1,1,1,2-tetrafluoroethane (R-134a) is used as the propellant.

According to a second aspect, the present invention provides for the usein a pharmaceutical composition comprising a drug, a propellant andethanol that is designed to be delivered using a medication deliverydevice and especially a metered dose inhaler of a propellant consistingessentially of and preferably consisting entirely of 1,1-difluoroethane(R-152a) in order to reduce the amount of ethanol required to dissolvethe drug in the pharmaceutical composition compared to the amount thatwould be needed if 1,1,1,2-tetrafluoroethane (R-134a) is used as thepropellant.

According to a third aspect, the present invention provides for the usein a medication delivery apparatus, especially a metered dose inhaler,that contains a pharmaceutical composition comprising a drug, apropellant and ethanol of a propellant consisting essentially of andpreferably consisting entirely of 1,1-difluoroethane (R-152a) to reducethe amount of ethanol required to dissolve the drug in thepharmaceutical composition compared to the amount that would be neededif 1,1,1,2-tetrafluoroethane (R-134a) is used as the propellant.

According to a fourth aspect of the present invention, there is provideda pharmaceutical solution for a medication delivery apparatus,especially a metered dose inhaler, comprising:

-   (a) a liquefied propellant component consisting essentially of and    preferably consisting entirely of 1,1-difluoroethane (R-152a);-   (b) ethanol; and-   (c) a drug component dissolved in the propellant/ethanol mixture    consisting of at least one drug selected from the group consisting    of beclomethasone dipropionate (BDP) and fluticasone propionate    (FP).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in vitro aerosolization performance of fluticasonepropionate (50 μg) solutions prepared in (i) R152a and ethanol (5% w/w)and (ii) R-134a and ethanol (13% w/w).

FIG. 2 shows in vitro aerosolization performance of beclomethasonedipropionate (250 μg) solutions prepared in (i) R152a and ethanol (2w/w) and (ii) R-134a and ethanol (4% w/w).

DETAILED DESCRIPTION

For the avoidance of doubt, in the pharmaceutical solution of thepresent invention, the propellant component is that component whichcomprises all the compounds in the solution that can function as apropellant. Similarly, the drug component is that component whichcomprises all the compounds in the solution that can function as amedicament. Thus, the only propellants and drugs in the pharmaceuticalsolutions of the invention are those that make up the propellantcomponent and the drug component respectively.

The propellant component of the pharmaceutical solution of the inventionconsists essentially of and preferably consists entirely of1,1-difluoroethane (R-152a). By the term “consists essentially of” wemean that at least 90 weight %, preferably at least 95 weight %, morepreferably at least 98 weight % and especially at least 99 weight % ofthe propellant component is 1,1-difluoroethane (R-152a). All percentagesare based on the total weight of the propellant composition.

The solubility of beclomethasone dipropionate (BDP) and fluticasonepropionate (FP) in the R-152a/ethanol mixture will obviously vary withtemperature, with each drug becoming progressively less soluble as thetemperature is lowered. However, in the pharmaceutical solutions of thepresent invention, the beclomethasone dipropionate and fluticasonepropionate can remain fully dissolved in the R-152a/ethanol mixture atthe lower temperatures at which MDIs have to work of 5° C.

It will be appreciated that the term “consists essentially of” doesallow for the presence of an additional propellant in the propellantcomponent, such as an additional hydrofluorocarbon or hydrocarbonpropellant, e.g. selected from R-227ea, R-134a, propane, butane,isobutane, dimethyl ether and R-32 (difluoromethane). However, and asexplained above, the propellant component will normally consist entirelyof 1,1-difluoroethane (R-152a).

The pharmaceutical solutions of the present invention are designed,particularly, to be contained in a pressurised aerosol canister to bedelivered using a MDI.

Conveniently, the pharmaceutical solutions of the invention have a GWPless than 1300, conveniently less than 1000, more conveniently less than800. Preferred solutions have a GWP of less than 650, e.g. less than250.

The pharmaceutical solution of the present invention will typicallycomprise from 79.0 to 98.0 weight % of the propellant component, from1.0 to 20.0 weight % of the ethanol and from 0.01 to 4.0 weight %, e.g.from 0.01 to 2.0 weight %, of the drug component. Preferredpharmaceutical solutions comprise from 87.0 to 98.0 weight % of thepropellant component, from 1.0 to 12.0 weight % of the ethanol and from0.01 to 2.0 weight % of the drug component. Especially preferredpharmaceutical solutions comprise from 93.0 to 98.0 weight % of thepropellant component, from 1.0 to 6.0 weight % of the ethanol and from0.01 to 2.0 weight % of the drug component. All percentages are based onthe total weight of the pharmaceutical solution.

Although the drug component may comprise a mixture of beclomethasonedipropionate (BDP) and fluticasone propionate (FP), ordinarily thepharmaceutical solution will comprise just one of the drugs.

The pharmaceutical solutions of the invention may comprise one or moreother additives of the type that are conventionally used in drugformulations for pressurised MDIs, such as valve lubricants. Where otheradditives are included in the pharmaceutical composition, they arenormally used in amounts that are conventional in the art.

The pharmaceutical solution of the present invention will preferablyconsist essentially of and more preferably will consist entirely of thespecified drug component, the specified propellant component andethanol.

Accordingly, in a preferred embodiment the present invention provides apharmaceutical solution for a medication delivery apparatus, especiallya metered dose inhaler, which consists essentially of:

-   (a) a liquefied propellant component consisting essentially of and    preferably consisting entirely of 1,1-difluoroethane (R-152a);-   (b) ethanol; and-   (c) a drug component dissolved in the propellant/ethanol mixture    consisting of at least one drug selected from the group consisting    of beclomethasone dipropionate (BDP) and fluticasone propionate    (FP).

As used in relation to the propellant component, the term “consistingessentially of” has the meaning ascribed above.

In stating that the pharmaceutical solution consists essentially of thethree specified components (a), (b) and (c) listed above, we mean thatat least 95 weight %, more preferably at least 98 weight % andespecially at least 99 weight % of the pharmaceutical solution is madeup of components (a), (b) and (c). In a particularly preferredembodiment, the entirety of the pharmaceutical solution is made up ofthe three components (a), (b) and (c).

The pharmaceutical solutions of the present invention are preferablypackaged in a suitable container, such as a pressurised aerosolcanister, which can be used in association with a drug delivery device,such as a MDI, to deliver the composition to a patient.

Accordingly, the present invention also provides a pressurised aerosolcanister comprising a pharmaceutical solution as discussed above. In apreferred embodiment, the aerosol canister is for use with a MDI.

The present invention also provides a MDI comprising a pressurisedaerosol canister containing a pharmaceutical solution as discussedabove.

The pharmaceutical solutions of the present invention are for use inmedicine for treating a patient suffering or likely to suffer from arespiratory disorder and especially asthma or a chronic obstructivepulmonary disease.

Accordingly, the present invention also provides a method for treating apatient suffering or likely to suffer from a respiratory disorder whichcomprises administering to the patient a therapeutically orprophylactically effective amount of a pharmaceutical solution asdiscussed above. The respiratory disorder may be asthma or a chronicobstructive pulmonary disease. The pharmaceutical solution is preferablydelivered to the patient using a MDI.

The pharmaceutical solutions of the invention can be prepared by asimple blending operation in which the R-152a propellant, the drug andthe ethanol are mixed together in the required proportions in a suitablemixing vessel. Mixing can be promoted by stirring as is common in theart. Conveniently, the R-152a propellant is liquefied to aid mixing. Ifthe pharmaceutical solution is made in a separate mixing vessel, it canthen be transferred to pressurised containers for storage, such aspressurised containers that are used as part of medication deliverydevices and especially MDIs.

The pharmaceutical solutions of the invention can also be preparedwithin the confines of a pressurised container, such as an aerosolcanister or vial, from which the solutions are ultimately released as anaerosol spray using a medication delivery device, such as a MDI. In oneversion of this method, a weighed amount of the drug is introduced intothe open container. A valve is then crimped onto the container and aliquid premix of the R-152a propellant and ethanol introduced throughthe valve into the container under pressure, optionally after firstevacuating the container through the valve. The whole mixture can thenbe treated to dissolve the drug in the propellant/ethanol mixture, e.g.by vigorous shaking or using an ultrasonic bath. In another version ofthis method, a weighed amount of the drug and the required amount ofethanol are introduced into the open container. A valve is then crimpedonto the container, optionally after mixing the drug and ethanoltogether, and the liquid R-152a propellant introduced through the valveinto the container under pressure, optionally after first evacuating thecontainer through the valve. The whole mixture can then be treated todissolve the drug in the propellant/ethanol mixture, e.g. by vigorousshaking or using an ultrasonic bath. Suitable canisters may be made ofplastics, metal or glass.

The canister may be filled with enough of the pharmaceutical solution toprovide for a plurality of dosages. The pressurized aerosol canistersthat are used in MDIs, typically contain 50 to 200 individual dosages.

The present invention is now illustrated but not limited by thefollowing Examples.

Example 1

A pressure solubility apparatus was constructed in order to determinethe solubility profiles of beclomethasone dipropionate (BDP) andfluticasone propionate (FP) in 1,1-difluoroethane (R-152a) and1,1,1,2-tetrafluoroethane (R-134a).

An excess of active pharmaceutical ingredient was placed into a pressurecylinder (300 cm³ stainless steel cylinder from Whitey, Inc.). A vacuumwas applied to the cylinder, which was then chilled using liquidnitrogen. Approximately 80 grams of either R-152a or R-134a propellantwas charged into the cylinder, which was then stored at 20° C. for 24hours.

A filtration unit comprising a 15 μm filter in-line with a 5 μm filterwas connected to the cylinder containing the excess of drug inpropellant. A second receiver pressure cylinder (150 cm³ stainless steelcylinder from Whitey, Inc.) was exposed to a vacuum and chilled usingliquid nitrogen, which was then connected to the filtration unit.Approximately 30 grams of liquid propellant containing drug in excesswas passed through the filtration unit and collected in the receiverpressure cylinder.

A modified piece of 3.2 mm (⅛″) tubing was connected to the end of thereceiver pressure cylinder, which was then attached to the stem of acontinuous valve crimped on to a glass bottle. The 3.2 mm (⅛″) tubingwas used to depress the stem of the valve and therefore, enable thecontents of the receiver pressure cylinder to be collected in the glassbottle. The glass bottle was weighed, following which one actuation wasshot into a dose content uniformity apparatus (DUSA) connected to avacuum pump operated at 30 L/min. The glass bottle was re-weighed andthe mass of drug collected in the DUSA was determined by highperformance liquid chromatography (HPLC).

This procedure was repeated (n=3) for each drug and propellantcombination.

HPLC was used to determine drug content. The HPLC consisted of a pump,column oven, column coupled to a UV detector (all Agilent 1200,Wokingham Berkshire, UK). A Hypersil BDS C18 column (Fisher,Loughborough, UK, 5 μm, 250×4.6 mm i.d.) was used for high-throughputanalysis of samples. The chromatographic conditions for each drug areprovided in Table 1.

TABLE 1 Contract samples analysed Pump Flow UV Column Rate MobileWavelength Temperature Drug (ml · min⁻¹) Phase (nm) (° C.)Beclomethasone 1.5 45% v/v 222 40 Dipropionate methanol, (BDP) 35% v/vacetonitrile and 20% v/v water Fluticasone 1.5 45% v/v 235 40 Propionate(FP) methanol, 35% v/v acetonitrile and 20% v/v water

The solubility of beclomethasone dipropionate (BDP) was analysed. Themean drug solubility (μg/g, ±Standard Deviation, S.D.) was found to be179.98±5.23 in a propellant comprising 100% R-152a, compared to a meandrug solubility of 26.65±0.08 in a propellant comprising 100% R-134a.

Example 2

The solubility of fluticasone propionate (FP) was assessed according tothe protocol described in Example 1. The mean drug solubility was foundto be 73.55±3.98 in a propellant comprising 100% R-152a, compared to asolubility of 14.27±1.66 in a propellant comprising 100% R-134a.

Example 3

An experiment was conducted to determine the amount of ethanol requiredto dissolve an amount of fluticasone propionate in a R-152a/ethanolmixture equivalent to that which would give rise to a 50 μg dose of thedrug on delivery from a MDI.

A series of glass vials were charged with 0.00869 g (8.69 mg) offluticasone propionate. R-152a propellant was then added to each vial,the amount being decreased from one vial to the next to compensate forincreasing amounts of ethanol. An amount of ethanol was then added toeach vial, with the amount being increased in increments from one vialto the next, in order to determine the minimum amount of ethanolrequired to dissolve the fluticasone propionate in the R-152a/ethanolmixture. The combined amounts of R-152a propellant and ethanol were suchthat the amount of fluticasone propionate in the R-152a/ethanol mixturewould give rise to a 50 μg dose of the drug on delivery from a MDI. Theamount of ethanol in the R-152a/ethanol mixture was increased from 1% byweight on the total weight of the R-152a/ethanol mixture in 1% w/wincrements. After adding the ethanol, each vial was sonicated in aneffort to dissolve the drug, stored at 20° C. and then examined visuallyto determine whether the drug had in fact dissolved. The first clearsolution gave us the amount of ethanol (% by weight on the total weightof the R-152a/ethanol mixture) required to achieve solubility at 20° C.It was determined that 5.0% w/w of ethanol was required to dissolve thefluticasone propionate.

Example 4

An experiment was conducted to determine the amount of ethanol requiredto dissolve an amount of beclomethasone dipropionate in a R-152a/ethanolmixture equivalent to that which would give rise to a 250 μg dose of thedrug on delivery from a MDI.

A series of glass vials were charged with 0.039 g (39 mg) ofbeclomethasone dipropionate. R-152a propellant was then added to eachvial, the amount being decreased from one vial to the next to compensatefor increasing amounts of ethanol. An amount of ethanol was then addedto each vial, with the amount being increased in increments from onevial to the next, in order to determine the minimum amount of ethanolrequired to dissolve the beclomethasone dipropionate in theR-152a/ethanol mixture. The combined amounts of R-152a propellant andethanol were such that the amount of beclomethasone dipropionate in theR-152a/ethanol mixture would give rise to a 250 μg dose of the drug ondelivery from a MDI. The amount of ethanol in the R-152a/ethanol mixturewas increased from 1% by weight on the total weight of theR-152a/ethanol mixture in 1% w/w increments. After adding the ethanol,each vial was sonicated in an effort to dissolve the drug, stored at 20°C. and then examined visually to determine whether the drug had in factdissolved. The first clear solution gave us the amount of ethanol (% byweight on the total weight of the R-152a/ethanol mixture) required toachieve solubility at 20° C. It was determined that 2.0% w/w of ethanolwas required to dissolve the beclomethasone dipropionate.

Comparative Example 5

An experiment was conducted to determine the amount of ethanol requiredto dissolve an amount of fluticasone propionate in a R-134a/ethanolmixture equivalent to that which would give rise to a 50 μg dose of thedrug on delivery from a MDI. Exactly the same procedure as described inExample 3 above was used except that R-134a was used as the propellant.It was determined that 13.0% w/w of ethanol (% by weight on the totalweight of the R-134a/ethanol mixture) was required to dissolve thefluticasone propionate.

Comparative Example 6

An experiment was conducted to determine the amount of ethanol requiredto dissolve an amount of beclomethasone dipropionate in a R-134a/ethanolmixture equivalent to that which would give rise to a 250 μg dose of thedrug on delivery from a MDI. Exactly the same procedure as described inExample 4 above was used except that R-134a was used as the propellant.It was determined that 4.0% w/w of ethanol (% by weight on the totalweight of the R-134a/ethanol mixture) was required to dissolve thebeclomethasone dipropionate.

Example 7

The in vitro aerosolization performance of fluticasone propionate andbeclomethasone dipropionate in (i) a R152a/ethanol mixture and (ii) aR-134a/ethanol mixture was investigated. The fluticasone propionatesolutions that were investigated were formulated to deliver a 50 μg doseof the drug. This equates to 0.83 mg of the drug per gram of liquid. Thebeclomethasone dipropionate solutions that were investigated wereformulated to deliver a 250 μg dose of the drug. This equates to 3.71 mgof the drug per gram of liquid. The amount of ethanol used in each casewas that required to dissolve the drug completely in thepropellant/ethanol mixture.

Solution formulations of fluticasone propionate and beclomethasonedipropionate were prepared in R-152a/ethanol and R-134a/ethanolmixtures. The drug was weighed directly into standard aluminium 19 mLcans (C128, Presspart, Blackburn, UK), to which an appropriate amount ofethanol was added to aid solubility of the drug on addition of thepropellant. The amount of ethanol included in the formulation for eachdrug is shown in Table 2. The slurry of the drug in ethanol was thensonicated for 60 minutes in order to disperse the drug in the ethanol.The cans were then crimped with a 504 valve (Bespak, Kings Lynn, UK)following which R-152a or R-134a as appropriate was filled into the cansthrough the valve using a manual Pamasol crimper/filler (Pamasol,Switzerland). Each can was then sonicated for 20 minutes to dissolve thedrug. Finally, all the cans were quarantined for 14 days, valve down, at22° C./44% RH before commencing testing of the final formulations.

TABLE 2 Ethanol content Ethanol Content Ethanol Content in R-134a inR-152a Drug (% w/w) (% w/w) Beclomethasone Dipropionate 4.0 2.0 (BDP,250 μg) Fluticasone Propionate 13.0 5.0 (FP, 50 μg)

It is evident from Table 2 above that significantly less ethanol wasrequired to dissolve the two drugs when R-152a was used as thepropellant rather than R-134a.

High performance liquid chromatography (HPLC) was used to determine drugcontent following aerosolization studies (see below). The HPLC machineconsisted of a pump, column oven, column coupled to a UV detector (allAgilent 1200, Wokingham, Berkshire, UK). A Hypersil BDS C18 column(Fisher, Loughborough, UK, 5 μm, 250×4.6 mm i.d.) was used. Thechromatographic conditions for each drug are shown in Table 3.

TABLE 3 Pump UV Column Flow Rate Mobile Wavelength Temperature Drug (ml· min⁻¹) Phase (nm) (° C.) Beclomethasone 1.5 45% v/v 222 40Dipropionate methanol, (BDP) 35% v/v acetonitrile and 20% v/v waterFluticasone 1.5 45% v/v 235 40 Propionate (FP) methanol, 35% v/vacetonitrile and 20% v/v water

The in vitro aerosolization performance of each formulation was studiedusing a Next Generation Impactor (NGI, Copley Scientific, NottinghamUK), which was connected to a vacuum pump (GE Motors, NJ, USA). Prior totesting, the cups of the NGI system were coated with 1% v/v silicone oilin hexane to eliminate particle bounce. For each experiment, threeactuations of the can were discharged into the NGI at 30 L·min⁻¹ as perpharmacopeia guidelines. Following aerosolization, the NGI apparatus wasdismantled and the actuator and each part of the NGI was washed downinto known volumes of the HPLC mobile phase. The mass of drug depositedon each part of the NGI was determined by HPLC. This procedure wasrepeated three times for each can, following which the emitted dose, thefine particle dose (FPD), the fine particle fraction of the emitted dose(FPF_(ED)), the mass median aerodynamic diameter (MMAD) and geometricstandard deviation (GSD) were determined.

The in vitro aerosolization performance of the fluticasone propionate(50 μg) solutions prepared in (i) R152a and ethanol (5% w/w) and (ii)R-134a and ethanol (13% w/w) are summarised in Table 4 below and shownin FIG. 1.

TABLE 4 Emitted Fine Particle Dose Dose (FPF_(ED)) MMAD ± Formulation(μg ± S.D.) (μg ± S.D.) (%) GSD R-134a/Ethanol 50.5 ± 1.8 20.6 ± 1.440.8 3.8 ± 4.2 (13.0% w/w) R-152a/Ethanol 49.5 ± 0.1 26.6 ± 1.8 53.7 3.2± 2.9  (5.0% w/w)

The emitted dose of the fluticasone propionate formulations prepared inR-134a/13.0% w/w ethanol and R-152a/5.0% w/w ethanol were similar.However, the fine particle dose and the fine particle fraction of theemitted dose were significantly (p<0.05) greater for the R-152a/ethanolformulation than for the R-134a/ethanol formulation. Furthermore, themass median aerodynamic diameter of the formulation produced usingR-152a and ethanol was smaller than that of the formulation producedusing R-134a and ethanol.

The in vitro aerosolization performance of the beclomethasonedipropionate (250 μg) solutions prepared in (i) R152a and ethanol (2%w/w) and (ii) R-134a and ethanol (4% w/w) are summarised in Table 5below and shown in FIG. 2.

TABLE 5 Emitted Fine Particle Dose Dose (FPF_(ED)) MAIAD ± Formulation(μg ± S.D.) (μg ± S.D.) (%) GSD R-134a/Ethanol 247.5 ± 0.5 122.3 ± 3.149.4 1.42 ± 2.12 (4.0% w/w) R-152a/Ethanol 250.2 ± 0.5 115.9 ± 0.2 46.31.49 ± 2.10 (2.0% w/w)

The emitted dose of the beclomethasone dipropionate formulationsprepared in R-134a/4.0% w/w ethanol and R-152a/2.0% w/w ethanol weresimilar. The fine particle dose and the fine particle fraction of theemitted dose were greater for the R-134a/ethanol formulation than forthe R-152a/ethanol formulation. However, the R-134a/ethanol formulationrequired twice as much ethanol to dissolve the beclomethasonedipropionate. The mass median aerodynamic diameter of the twoformulations were also similar.

It is evident from the above aerosolization studies that less ethanol isneeded to dissolve both fluticasone propionate and beclomethasonedipropionate when R-152a is used as the propellant rather than R-134a.This is an important advantage. In addition, the formulations that useR-152a exhibit useful aerosolization performance. Indeed, whenfluticasone propionate is used as the drug, better aerosolizationperformance is achieved when R-152a is used as the propellant ratherthan R-134a.

1. A pharmaceutical solution for delivery using a medication deliveryapparatus to treat a respiratory disorder comprising: (a) a liquefiedpropellant component at least 90 weight % of which is 1,1-difluoroethane(R-152a); (b) 1.0 to 20.0 weight % of ethanol based on the total weightof the pharmaceutical solution; and (c) a drug component dissolved inthe propellant/ethanol mixture consisting of at least one drug selectedfrom the group consisting of beclomethasone dipropionate (BDP) andfluticasone propionate (FP).
 2. The pharmaceutical solution of claim 1,wherein at least 95 weight % of the propellant component is1,1-difluoroethane (R-152a) based on the total weight of the propellantcomponent. 3-4. (canceled)
 5. The pharmaceutical solution of claim 1,wherein the propellant component is entirely 1,1-difluoroethane(R-152a).
 6. The pharmaceutical solution of claim 1, wherein at least 95weight % of the solution is made up of components (a), (b) and (c). 7.The pharmaceutical solution of claim 6, wherein at least 98 weight % ofthe solution is made up of components (a), (b) and (c). 8-9. (canceled)10. The pharmaceutical solution of claim 1, wherein the entirety of thesolution is made up of components (a), (b) and (c).
 11. Thepharmaceutical solution of claim 1, wherein the drug component isbeclomethasone dipropionate (BDP). 12-14. (canceled)
 15. Thepharmaceutical solution of claim 1, wherein the ethanol comprises from1.0 to 6.0 weight % of the total weight of the pharmaceutical solution.16-18. (canceled)
 19. The pharmaceutical solution of claim 1 whichcomprises from 93.0 to 98.0 weight % of the propellant component, from1.0 to 6.0 weight % of the ethanol and from 0.01 to 2.0 weight % of thedrug component.
 20. A sealed container that contains a pharmaceuticalsolution as claimed in claim
 1. 21-22. (canceled)
 23. A method fortreating a patient suffering or likely to suffer from a respiratorydisorder which comprises administering to the patient a therapeuticallyor prophylactically effective amount of a pharmaceutical solution asclaimed in claim
 1. 24-25. (canceled)
 26. The use of a propellantconsisting essentially of or consisting entirely of 1,1-difluoroethane(R-152a) in a pharmaceutical composition comprising a drug, thepropellant and ethanol in order to reduce the amount of ethanol requiredfor dissolving the drug in the pharmaceutical composition compared tothe amount that would be needed if 1,1,1,2-tetrafluoroethane (R-134a) isused as the propellant. 27-31. (canceled)
 32. The pharmaceuticalsolution of claim 1, wherein the drug component is fluticasonepropionate (FP).
 33. The pharmaceutical solution of claim 1, wherein atleast 99 weight % of the propellant component is 1,1-difluoroethane(R-152a) based on the total weight of the propellant component.
 34. Thepharmaceutical solution of claim 6, wherein at least 99 weight % of thesolution is made up of components (a), (b) and (c).
 35. Thepharmaceutical solution of claim 1, wherein the ethanol comprises from1.0 to 12.0 weight % of the total weight of the pharmaceutical solution.